Combined Metalation-Palladium-Catalyzed Cross Coupling Strategies. A Formal Synthesis of the Marine Alkaloid Amphimedine

Article abstract of DOI:10.1021/jo00107a004

The synthesis of 5-(4-pyridyl)benzo<2,7>naphthyridin-4-one (4), an intermediate previously employed in a total synthesis of the marine alkaloid, amphimedine (2), is reported.The route comprises the Pd-catalyzed Suzuki cross coupling of pyridylborane 21 with 2-iodoaniline to give the azabiaryl 22, which upon LDA-mediated cyclization and triflation leads to benzonaphthyridine 5.Stille cross coupling of 5 with pyridylstannane 24 affords the pyridylbenzonaphthyridine 25, which upon BBr3 treatment leads to the target molecule 4.Pyridine directed ortho metalation chemistry leading to halonicotinate ester 12 and amides 14a,b and cross coupling to benzonaphthyridinones 17, 18 (one-pot procedure) and azabiaryls 20a,b are also reported.